Rett Syndrome (RTT, MIM 312750) is an X-linked neuro-developmental condition characterized by a variety of clinical features, most notably loss of hand use and language between 6-18 months of life. Furthermore, affected individuals have prominent hand stereotypes, growth failure, cognitive impairment, autonomic dysfunction and seizures. RTT is caused by mutations in the gene encoding Methyl-CpG Binding Protein 2 (MECP2). An animal model generated in the laboratory of Dr. Zoghbi recapitulates many of the clinical features of RTT and thus is a useful disease model. Importantly, many of the movement abnormalities seen in the human disease are present in the animal model. This proposal is based on the hypothesis that specific clinical features in RTT are attributable to MeCP2 dysfunction within specific neuron populations. Specifically, MeCP2 dysfunction within the nigrostriatal dopaminergic system is the cause of the movement abnormalities in the disease. Therefore, this proposal seeks to explore the dopaminergic system in an animal model of RTT. The Specific Aims of this grant are to: 1) Characterize the dopaminergic system in RTT mice by studying the neurochemical composition and behavioral response of RTT mice to pharmacological challenge;2) Determine the consequence of loss of MeCP2 function exclusively in the dopaminergic system;3) Analyze gene expression changes within pre- and post-synaptic dopamine neurons in the RTT mouse model. These studies will explore the dysfunction of the dopamine system in RTT and will illuminate possible therapeutic strategies for the movement abnormalities found in RTT syndrome. Furthermore, they will shed light on the genetic mechanisms generating movement disorders in general. This insight may pave the way for future therapeutic strategies for other movement disorders such as: Parkinson's disease or Huntington's disease.